Abstract Neuropathic pain reflects a myriad of changes in the periphery, spinal cord, and subcortical and cortical structures. Interestingly, despite this baffling array of changes, many approved treatments for neuropathic pain recruit, augment, or mimic bulbospinal inhibition including morphine, noradrenaline (NA) re-uptake inhibitors, and clonidine. Although clinical studies suggest a baseline deficit of descending inhibition in patients with neuropathic pain, we believe that activation of this pathway is key to its treatment. GBP (GBP) is commonly used as a safe and effective treatment of neuropathic pain. GBP analgesia depends on an interaction with the 124 subunit of calcium channels, but the circuits activated by GBP for analgesia are not entirely known. We and others recently demonstrated that GBP activates the descending bulbospinal noradrenergic pathway after nerve injury and after surgical incision in rodents. We also demonstrated that orally administered GBP significantly increases NA concentration in cerebrospinal fluid and decreases opioid requirements after surgery in patients with chronic pain. These findings argue that activation of descending inhibition, rather than peripheral or spinal actions, is pivotal for GBP analgesia. The goals of this proposal are to identify the mechanisms by which GBP activates descending inhibition. Since descending inhibitory noradrenergic axons originate from the locus coeruleus (LC) and adjacent nuclei in the brainstem, we focus on the LC as a target of action of GBP. Initially, we will utilize immunocytochemistry and microdialysis methods in LC to examine the local mechanisms by which GBP activates NA neurons, focusing on the roles of GABA and glutamate inputs. Secondly, we will perform behavioral tests and measure NA content in microdialysis samples from spinal dorsal horn to examine the link between actions of GBP to reduce hypersensitivity after nerve injury and to increase spinal NA release, as a consequence of activation of NA neurons in LC. The proposed studies will not only provide critical tests of our hypothesis of this primary site and mechanism of action of GBP for analgesia but also probe mechanisms by which the descending NA system can be recruited to treat neuropathic pain. PUBLIC HEALTH RELEVANCE: Gabapentin is widely used to treat chronic pain, but how it works is not well understood. We recently found that gabapentin activates a natural pain-relief mechanism, and in this proposal, we will study how gabapentin stimulates the body's own pain relieving system to work in chronic pain.